Interplay between short-chain fatty acids and the circadian clock in the rhythmicity of contractility and hormone release in the gut

Our bodies keep track of time using circadian clocks to anticipate predictable 24-h environmental changes. The circadian system and the timing of food intake dictate diurnal rhythms in the microbiota. In turn, microbial metabolites such as short-chain fatty acids (SCFAs) can entrain the circadian system. The aim of this PhD thesis was to identify the role of the circadian clock in the diurnal rhythms of SCFA concentrations and their effects on gut contractility and on the release of the hunger hormone ghrelin.  

In wild type mice, SCFA levels in caecum, distal colon and plasma showed diurnal rhythms. Caecal and plasma SCFAs oscillated in phase, while colonic SCFA concentrations peaked 9h later. Colonic SCFA concentrations fluctuated in phase with mRNA expression of the SCFA receptor Ffar3 in the colonic myenteric plexus. SCFAs inhibited neural contractions of colonic smooth muscle strips diurnally, and their effect peaked in the resting phase, together with SCFA levels and Ffar3 expression. The effect of SCFAs on ghrelin release from stomach and colon full-thickness strips also showed diurnal rhythmicity, with higher responses during the resting phase. However, SCFAs stimulated ghrelin release from stomach strips, while they inhibited ghrelin release from the colon. In mice lacking the core clock gene Bmal1, no fluctuations in SCFA levels, Ffar3 expression and neural responses to SCFAs were observed. In addition, the effects of SCFAs on ghrelin release were lost. Since Bmal1-/- mice eat continuously and do not show a typical day-night feeding rhythm, we studied whether this was the main cause for the loss of SCFA rhythms and of their effect on ghrelin release. Night-time restricted feeding of Bmal1-/- mice restored fluctuations in SCFA concentrations in the caecum and colon, and restored the inhibitory effect of SCFAs on colonic ghrelin release. However, local entrainment of other clock genes might contribute to the observed effects, as restricted feeding increased colonic Clock mRNA expression.

To conclude, in this PhD thesis, we demonstrated that 24-h fluctuations of SCFAs act as a signal that integrates cues from the circadian clock and feeding time to regulate diurnal rhythms in SCFA receptor expression, gut contractility and ghrelin release.